System and method for locating and identifying the functional nerves innervating the wall of arteries and catheters for same

ABSTRACT

System and method for locating and identifying nerves innervating the wall of arteries such as the renal artery are disclosed. The present invention identifies areas on vessel walls that are innervated with nerves; provides indication on whether energy is delivered accurately to a targeted nerve; and provides immediate post-procedural assessment of the effect of energy delivered to the nerve. The method includes at least the steps to evaluate a change in physiological parameters after energy is delivered to an arterial wall; and to determine the type of nerve that the energy was directed to (none, sympathetic or parasympathetic) based on the evaluated results. The system includes at least a device for delivering energy to the wall of blood vessel; sensors for detecting physiological signals from a subject; and indicators to display results obtained using this method. Also provided are catheters for performing the mapping and ablating functions.

This application is a Continuation Application of U.S. Ser. No.16/172,896, filed Oct. 29, 2018, published as US2019/0076191 A1, andissued as patent Ser. No. 10/842,559, which is a ContinuationApplication of U.S. Ser. No. 15/636,960, filed Jun. 29, 2017, publishedas US 2017/0296265 A1, and issued as patent Ser. No. 10/111,708, whichis a Continuation Application of U.S. Ser. No. 15/195,998, filed Jun.28, 2016, published as US 2016/0374568 A1, and issued as U.S. Pat. No.9,723,998, which is a Continuation Application of U.S. Ser. No.14/691,553, filed Apr. 20, 2015, published as US 2015/0289770 A1, andissued as U.S. Pat. No. 9,375,154, which is a Continuation Applicationof U.S. Ser. No. 14/241,061, filed Feb. 25, 2014, published as US2014/0213873 A1, and issued as U.S. Pat. No. 9,014,821, which is theNational Stage of International Application No. PCT/IB2012/054310, filedAug. 24, 2012, published as WO 2013/030743 A1, which claims benefit ofU.S. Ser. No. 61/609,565, filed Mar. 12, 2012 and U.S. Ser. No.61/527,893, filed Aug. 26, 2011. The contents of the precedingapplications are hereby incorporated in their entireties by referenceinto this application. Throughout this application, various publicationsare referenced. Disclosures of these publications in their entiretiesare hereby incorporated by reference into this application in order tomore fully describe the state of the art to which this inventionpertains.

FIELD OF THE INVENTION

This invention relates to a system and method for accurate and preciselocation and identification of areas innervated with sympathetic andparasympathetic related nerves on an arterial wall during and after anenergy delivery process. This invention also relates to catheter systemsspecifically designed for use in renal nerve mapping and ablation.

BACKGROUND OF THE INVENTION

Congestive heart failure, hypertension, diabetes, and chronic renalfailure have many different initial causes; however, all follow a commonpathway in their progression to end-stage diseases. The common pathwayis renal sympathetic nerve hyperactivity. Renal sympathetic nerves serveas the signal input pathway to higher sympathetic centers located in thespinal cord and brain via afferent renal nerve activity, increasingsystemic sympathetic tone; meanwhile, through efferent activity, renalnerves and arteries participate in sympathetic hyperactivity in responseto signals from the brain, further increasing systemic sympathetic tone(Dibona and Kopp, 1977). Sympathetic activation can initially bebeneficial but eventually becomes maladaptive. In a state of sympathetichyperactivity, a number of pathological events take place: abnormalitiesof hormonal secretion such as increased catecholamine, renine andangiotensin II levels, increased blood pressure due to peripheralvascular constriction and/or water and sodium retention, renal failuredue to impaired glomerular filtration and nephron loss, cardiacdysfunction and heart failure due to left ventricular hypertrophy andmyocyte loss, stroke, and even diabetes. Therefore, modulation(reduction/removal) of this increased sympathetic activity can slow orprevent the progression of these diseases. Recently, renal nervedenervation using high radio frequencies has become a recognized methodto treat drug resistant hypertension (Ester et al., 2010 and Krum etal., 2009) and glucose metabolism abnormality (Mahfoud, 2011). However,certain methodologies by which renal nerve ablation or denervations areperformed are either primitive, or are conducted in a manner whereby themedical professional operates with undue uncertainty respecting thelocation of the renal nerves critical in the disease pathway. Thepresent invention seeks to rectify certain of these problems.

Renal Sympathetic Nerve Hyperactivity and Hypertension

Renal sympathetic nerve hyperactivity's contribution to the developmentand perpetuation of hypertension has been systematically investigated.This connection has been explored due in large part to the fact that,despite the availability of various pharmaceutical products andcombination pharmaceutical products, and resources to assist patients'lifestyle changes, the rate of treatment of hypertension has remainedsurprisingly low. In particular, approximately ⅓ of hypertensivepatients are not fully responsive to even optimized drug therapy and themeasured blood pressure range amongst this cohort remains abnormal. Thismanifestation is called drug resistant hypertension. In approximatelyhalf of hypertensive patients, blood pressure remains higher thanaccepted treatment target levels. Amongst these patents with “essential”hypertension (i.e. persistent and pathological high blood pressure forwhich no specific cause can be found), it has been suggested thatunderlying pathophysiologies which are non-responsive to currenttreatment regimens exist. Further, it has been noted in such patientsthat efferent sympathetic renal nerve outflow stimulates renin release,increases tubular sodium reabsorption, and reduces renal blood flow,while afferent nerve signals from the kidney modulate centralsympathetic outflow and thereby contribute to regulation of sodium andwater metabolism, vascular tone/resistance and blood pressure.

Various data have confirmed the positive effects of renal nerve blockingon decreasing hypertension; data have further confirmed the connectionbetween increased sympathetic nervous system activity and hypertension.In particular, studies have shown renal dysfunction as a mechanism ofincreased sympathetic nervous system activity leading to hypertension(Campese, 2002; Ye, 2002), that blocking renal nerve activity controlshypertension in animals with chronic renal insufficiency (Campese,1995), and that surgical renal denervation performed to eliminateintractable pain in patients with polycystic kidney disease alsoeliminates hypertension (Valente 2001). Additional studies haveidentified increased noradrenaline spillover into the renal vein as theculprit in essential hypertension (Esler et al., 1990), and have shownthat denervation by nephrectomy eliminates hypertension in humans ondialysis with severe hypertension refractory to multi-drug therapy(Converse 1992). Renal denervation has also been shown to delay orprevent the development of many experimental forms of hypertension inanimals (e.g. spontaneously hypertensive rats (SHR), stroke prone SHR,New Zealand SHR, borderline hypertensive rats (BHR), Goldblatt 1K, 1C(rat), Goldblatt 2K, 2C (rat), aortic coarctation (dogs), aortic nervetransection (rat), DOCA-NaCL (rat, pig), Angiotensin II (rat, rabbit),fat feeding—obesity (dog), renal wrap (rat))(DiBona and Kopp, 1997),

Renal Sympathetic Nerve Hyperactivity, Insulin Sensitivity and GlucoseMetabolism

Renal nerve hyperactivity is also posited to play a role in insulinsensitivity and glucose metabolism. Specifically, an increase innoradrenaline release accompanying renal nerve hyperactivity results inreduced blood flow, which in turn is associated with reduced glucoseuptake. This indicates an impaired ability of cells to transport glucoseacross their membranes. Renal nerve hyperactivity is related to aneurally mediated reduction in the number of open capillaries, so thatthere is an increased distance that insulin must travel to reach thecell membrane from the intravascular compartment. Insulin-mediatedincreases in muscle perfusion are reduced by approximately 30% ininsulin-resistant states. Consequently there is a direct relationshipbetween muscle sympathetic nerve activity and insulin resistance, and aninverse relationship between insulin resistance and the number of opencapillaries. (Mahfoud, et al., 2011). Renal sympathetic nervehyperactivity is thus associated with certain aspects of diabetesmellitus and/or metabolic syndrome; sympathetic hyperactivity inducesinsulin resistance and hyperinsulinemia, which in turn producesadditional sympathetic activation. Studies have been performedevaluating the effects of renal denervation on diabetic criteria.

A study by Mahfoud et al. (2011) tested the effect of renal denervationon patients who had type 2 diabetes mellitus, as well as high bloodpressure of ≥160 mm Hg (or ≥150 mm Hg for patients with type 2 diabetesmellitus) despite being treated with at least 3 anti-hypertensive drugs(including 1 diuretic). At baseline and at follow-up visits taking placeat one (1) and three (3) months after the procedure, blood chemistry,and fasting glucose, insulin, C peptide, and HbA1c were measured, whilean oral glucose tolerance test (OGTT) was performed at baseline andafter 3 months. Three months after denervation, diabetic indicators hadsubstantially improved. Insulin sensitivity increased significantlyafter renal denervation. After the procedure, 7 of 25 patients showedimprovement in OGTT. The Mahfoud et al. study thus conclusivelydemonstrated that the renal sympathetic nervous system is an importantregulator of insulin resistance and shows that renal nerve ablationsubstantially improves insulin sensitivity and glucose metabolism.During 1950s, surgical sympathectomy was utilized in humans as atreatment for severe hypertension before the availability ofantihypertensive medicine (Smithwick and Thompson, 1953). However, suchsurgical renal denervation was extremely invasive and involved a majorsurgical procedure; therefore, it had great limitations in clinicalpractice (DiBona, 2003).

Recently, endovascular catheter technologies have been preferablyutilized to create selective denervation in the human kidney. The renalnerves primarily lay outside the vessel tunica media, within the renalartery adventitial space. Consequently, radiofrequency energy, laserenergy, high intensive focused ultrasound and alcohol can be deliveredto renal artery walls, and cryoablative techniques likewise utilized onrenal artery walls, via the renal artery lumen, to ablate sympatheticrenal nerves. The first human study of renal nerve ablation by cathetermethodologies took place on hypertensive patient test subjects in 2009.Patient test subjects were enrolled whose standing blood pressure (SBP)was more than or equal to 160 mmHg despite the patient being on morethan three anti-hypertensive medications (including diuretics), or whohad a confirmed intolerance to anti-hypertensive medications (Krum etal., 2009). In this study of forty-five (45) patients overall baselinepatient blood pressure consisted of (mmHg) of 177/101±20/15.

In order to assess whether renal denervation was effectively performed,after renal nerve ablation, renal noradrenaline spillover was measuredto determine the success of the sympathetic denervation. Blood pressurewas measured at baseline, and at 1 month, 3 months, 6 months, 9 months,and 12 months after the procedure. At each time point, decreases in bothsystolic and diastolic pressure were registered, with decreasescontinuing with the passage of time. Post-procedure, an overall decreasein total body noradrenaline spillover of 28% (p=0.043) was shown amongstthe 45 test subjects, of which approximately one third was attributableto the renal sympathetic denervation.

Current Protocols in Renal Denervation

After the Krum et al. study, there have been established certainaccepted methodologies for performing renal nerve ablation throughcatheter means, though said methodologies comprise some variation.Typically, renal nerve ablation comprises catheter-based methods inwhich a patient is administered four (4) to six (6) two-minute radiofrequency (RF) treatments per renal artery, with the radio frequencybeing generated by a radio frequency (RF) generator, which is automated,low-power, and has built-in safety algorithms. The radio frequencies,usually of 5-8 waits, are administered by catheter in the renal arterythrough movement of the catheter distal to the aorta to proximal to theaorta with application of the radio frequencies in spaced increments of5 mm or more.

In the aforementioned Mahfoud et al. diabetes study, the followingspecific ablation protocol was followed: a treatment catheter wasintroduced into each renal artery by use of a renal double curve or leftinternal mammary artery guiding catheter; radiofrequency ablationslasting up to 2 minutes each were applied with low power of 8 watts toobtain up to 6 ablations separated both longitudinally and rotationallywithin each renal artery. Treatments were delivered from the firstdistal main renal artery bifurcation to the ostium. Catheter tipimpedance and temperature were constantly monitored, and radiofrequencyenergy delivery was regulated according to a predetermined algorithm.

Functionally, the optimized goal of ablation of the renal arteries is toselectively disable the renal sympathetic (both afferent and efferent)nerves without impairing sympathetic signaling to other organs, and toprecisely deliver energies to the locations in which renal sympatheticnerves are distributed in order to denervate the nerves. At present,renal nerve ablation is done in a “blind” fashion—that is, before theablation radiofrequency is delivered, the physician who performs theprocedure does not know where the renal sympathetic nerves aredistributed so that the whole length of renal artery is ablated;furthermore, whether renal nerves have really been ablated or not canonly be confirmed by measuring a secondary effect—i.e. norepinephreinespillover, after completion of the procedure. At present, approximately89% of patients respond to renal denervation treatment in a small andvery selective patient population (Krum et al., 2009 and Esler et al.2010). However, recent data showed that the responder rate can be as lowas less than 50% among treated patients (Medical devices: pg 1-2, Feb.22, 2012). In some cases, treatment failures may be due to regenerationof renal nerves (Esler et al., Lancet 2010. p. 1908), while in others,treatment failures may be due to failure to correctly target andsufficiently complete ablation of the renal nerves. Therefore, methodsto precisely detect where renal nerve distribution occurs along therenal arteries, so that ablation targets can be provide to physicians,and to monitor clinically relevant indices (such as blood pressure,heart rate and muscle sympathetic nerve activity) to assess whetherefficient ablations are delivered, are urgently needed. As abovediscussed, renal afferent and efferent nerve system serves as a commonpathway for sympathetic hyperactivity, therefore stimulation of renalnerve can cause increases in blood pressure and changes in heart rate.Changes in heart rate can be either increased due to direct stimulationof sympathetic nerves, or decreased blood pressure due to an indirectreflex regulation via baroreflex.

An improved methodology would involve a renal nerve mapping approach bywhich individual segments of the renal artery are stimulated by a lowpower electrical current while blood pressure, heart rate and musclesympathetic nerve activity were measured. If measurable changes in bloodpressure, heart rate and muscle sympathetic nerve activity are detected,such as increases in blood pressure or changes in heart rate ordecreases in muscle sympathetic nerve activity, there is a reasonableexpectation that ablation at that site should be performed so as todestroy nerve fibers in more precise way, and consequently, improve theclinical measures desired. These improved renal nerve mapping andcatheterization technologies would seek to minimize unnecessary ablationin the types of denervation procedures described, guide operators toperform renal ablation procedures, and to optimize clinical outcomes ofrenal nerve ablation for treatment of hypertension, heart failure, renalfailure and diabetes.

Anatomical Mapping and Targeting in Renal Nerve Ablation

Anatomically, the nerves carrying fibers running to or from the kidneyare derived from the celiac plexus (a/k/a the solar plexus) and itssubdivisions, lumbar splanchic nerves, and the intermesenteric plexus(DiBona and Kopp, 1997. p. 79). The celiac plexus consists of thesuprarenal ganglion (i.e. the aorticorenal ganglion), the celiacganglion, and the major splanchnic nerves. The celiac ganglion receivescontributions from the thoracic sympathetic trunk (thoracic splanchnicnerves), and the vagus nerves (DiBona and Kopp, 1997, p. 79).

The suprarenal ganglion gives off many branches toward the adrenalgland, some of which course along the adrenal artery to the perivascularneural bundles around the renal artery entering the renal hilus; otherbranches enter the kidney outside the renal hilar region. The majorsplanchic nerve en route to the celiac ganglion gives off branches tothe kidney at a point beyond the suprarenal ganglion. The celiacganglion gives off branches to the kidney that run in the perivascularneural bundles around the renal artery entering the renal hilus (DiBona.and Kopp, 1997, p. 79).

The lumbar and thoracic splanchic nerves are derived from the thoracicand lumbar paravertebral sympathetic trunk, respectively. They providerenal innervation via branches that go to the celiac ganglion but alsovia branches that go to the perivascular neural bundles around the renalartery entering the renal hilus (DiBona and Kopp, 1997, p. 79).

The intermesenteric plexus, containing the superior mesenteric ganglion,receives contributions from the lumbar splanchnic nerves and gives offbranches that often accompany the ovarian or testicular artery beforereaching the kidney (DiBona and Kopp, 1997, p. 79). The renal nervesenter the hilus of the kidney in association with the renal artery andvein (DiBona and Kopp, 1997, p. 81). They are subsequently distributedalong the renal arterial vascular segments in the renal cortex and outermedulla, including the interlobar, arcuate, and interlobular arteriesand the afferent and efferent glomerular arterioles (DiBona. and Kopp,1997, p. 81).

While the renal nerve architecture is of paramount consideration beforeablation can take place, individual renal architecture must be carefullyconsidered before catheterization for denervation can be contemplated.As noted with respect to the Krum et al./Esler et al. studies,eligibility for catheterization was determined in part by an assessmentof renal artery anatomy, renal artery stenosis, prior renal stenting orangioplasty, and dual renal arteries. Not only is aberrant or unusualrenal architecture an impediment to catheterization in and of itself,but normal variation in renal architecture may prove challenging,especially when an off-label catheter system (i.e. a catheter notspecifically designed for renal artery ablation per se) is used. Therisks of renal catheterization with sub-optimal catheter systems mayinclude the rupture of renal arteries due to coarse or jaggedmanipulation of such catheter tips through delicate tissue, rupture ofand/or damage to the artery wall or renal artery endothelium due toexcessive ablation energy applied, and dissection of the artery.Therefore, catheter systems specially designed for renal architectureand common aberrations in renal architecture are desirable, in orderthat a large spectrum of the eligible refractory patient population betreated.

Catheter Systems

Certain catheter systems designed for coronary artery systems aresimilar to those which may be used in renal nerve ablation inparticular, ablative catheter systems designed for coronary artery usewhich are tailored to remedy tachycardia may be used for renal nerveablation procedures. As such, these systems typically contain electrodeswhich are designed to assess the pre-existing electric current in thecardiac tissue through which the catheter electrodes are being passed.In contrast, ideal catheter systems for renal denervation wouldoptimally be engineered with dual functions: to map renal nervedistribution and stimulate renal nerve activity by providing electricalstimulation so that a physician operator may assess in real-time patientphysiological changes occurring as a result of said electricalstimulation and renal denervation. However, such catheters have notpreviously been developed.

Known catheter systems often possess multiple functionalities forcardiac uses. Certain notable catheter systems on the market include thefollowing:

Ardian Symplicity® Catheter System

The current catheter system utilized for renal ablation, comprising bothan ablation catheter and radio frequency generator, i.e. the Symplicity®Catheter System, is specially designed by Ardian Inc. (Mountain View,Calif., USA). However, the Symplicity® catheter does not possess mappingfunctions and ablation is its only function; and secondly, such cathetersystems (as well as angioplasty and distal protection devices forangioplasty) were designed for coronary and carotid arterysystems—hence, these systems would be used “off-label” for renal nerveablation and denervation to treat hypertension, heart failure, renalfailure and diabetes.

The fact that some cases of hypertension are resistant to treatment bypure pharmacological means has reignited the use of invasive techniquesin treating these cases. Historically, surgical renal denervation wasthe prominent treatment for severe cases of hypertension prior to theintroduction of orally administered anti-hypertensive drugs (Smithwickand Thompson, 1953). This type of conventional surgery was, however,extremely invasive and involved a major surgical procedure which greatlylimits it practicality (DiBona, 2003). At least two clinical studieshave, to a certain extent, provided support to the use of minimallyinvasive catheter-based radiofrequency (RF) renal nerve ablation in thetreatment of resistant hypertension (Krum et al., 2009; Esler et al.,2009). Patients with hypertension resistant to the availableanti-hypertensive drugs were selected for these studies and thisinterventional procedure demonstrated a 89% clinical success rate inlowering their blood pressure in a small and very selective patientpopulation.

While there is growing interest in using such minimal invasiveinterventional techniques for treatment of hypertension, all systems onthe market, including the Ardian Symplicity® Catheter System, are notoptimally designed for this purpose. There are apparent shortcomings,even in the Ardian Symplicity® Catheter System, that limit the certaintyof the interventional outcome.

An important aspect not considered in the current interventional systemsand techniques, is the precision and accuracy in locating and deliveringan effective dose of energy to a suitable ablation spot in the arterialwall. The current commonly accepted procedures for performing renalnerve ablation via catheters typically consists the steps ofadministering to the arterial wall 4 to 6 ablations, each made by 2minutes of RF energies and spaced both longitudinally and rotationallyalong the inner wall of each renal artery. The ablations had to bedelivered “blindly” in this helical manner because the exact location ofthe nerves innervating the renal artery with respect to the ablationcatheter is unknown before and during the delivery of the ablationenergy. An inaccurately directed dose of energy not only causesunnecessary damage to healthy tissues and non-sympathetic nerves butmore importantly could not provide the promised solution forhypertension which the interventional procedure was intended for. Infact, in certain clinical settings other than the two published studies,the responder rate of the current “blind” type of interventionalprocedure could go as low as 50% (Medical devices: pg 1-2, Feb. 22,2012).

Theoretically, precise nerve ablation in the wall of an artery could beachieved by mapping the location of the nerves innervating the arterialwall prior to delivery of the dose of energy. By monitoringphysiological parameters associated with the autonomic nervous systemssuch as the blood pressure, heart rate and muscle activity while astimulus is delivered to a selected location on the arterial wall, thepresence of autonomic nerves in the immediate vicinity of this locationwill be reflected from the changes in the monitored physiologicalparameters (Wang, Pub No. US 2011/0306851 A1, issued as U.S. Pat. No.8,702,619).

Further, the sympathetic and parasympathetic nerves of the autonomicnervous system often exert opposite effects in the human body includingtheir control on blood pressure and heart rate. While ablation of thesympathetic nerves innervating the arterial walls will relievehypertension, there is an equally possible chance that other tissuessuch as parasympathetic nerves are ablated in the “blind” type ofinterventional procedure. The result for decreasing or removal of nerveactivity blindly may worsen the hypertension as could be inferred fromseveral animal studies (Ueda et al., 1967; Beacham and Kunze, 1969; Aarsand Akre, 1970; Ma and Ho, 1990; Lu et al. 1995).

The cause of failure in the current treatment was attributed toregeneration of the nerves after the ablation (Esler et al., 2010) andmay also be related to both the inability to deliver the dose of energyto the targeted nerve and an insufficient dose of energy delivered foreffective ablation. At present, the success of renal denervation is onlyassessed by the measurement of a secondary effect known asnorepinephrine spillover at least days after the interventionalprocedure Krum et al., 2009) and lack a method for immediatepost-procedural assessment. In order to improve the success rate of theinterventional procedure, it is important to not only locate suitableablation spots on the arterial wall, but also ensure that the energy isprecisely and accurately delivered to a targeted nerve during theablation process, and confirm immediately after the ablation that thedosage of energy delivered has effectively ablated the targeted nerve.

In response to the shortcomings of the current system and methods fornerve ablation, the present invention introduces improvements byproviding a system and methods for accurate and precise location ofsuitable ablation spots on a renal arterial wall; ensuring sufficientablation energy is accurately directed into a targeted nerve and toconduct immediate post-procedural assessment of nerve ablation. Acatheter system optimal for renal nerve mapping is also provided by thisinvention.

SUMMARY OF THE INVENTION

It was with the preceding needs in mind that the present invention wasdeveloped. Embodiments of the disclosure are directed to system andmethod for accurate and precise location of areas innervated with nerveson an arterial wall; ensuring sufficient energy is accurately directedinto a targeted nerve to elicit a desired response such as stimulationand ablation; and to conduct immediate post-procedural assessment of asufficient nerve ablation. Further, the embodiments of the disclosureare also directed to provide an interface for clear representation ofthe location and type of nerves that are innervating the location beingprobed on the arterial wall.

The present invention provides a method for identifying the presence offunctional sympathetic and parasympathetic nerves innervating thearterial walls in a human body with respect to the location of a dose ofenergy. The method comprises one or more of the steps of preparing abaseline of one or more of physiological parameters prior to thedelivery of a dose of energy to the arterial wall; delivering a dose ofenergy to the arterial wall; detecting the physiological changes as aresult of the delivered energy; rating the change based on a set ofempirically pre-determined values; and determining if the area where theenergy was delivered lies in the vicinity of functioning sympathetic orparasympathetic nerves based on the ratings.

In one embodiment, said method is used for locating suitable nerveablation sites relevant to baroreflex including both sympathetic andparasympathetic systems in arterial walls prior to a nerve ablationprocedure. In certain embodiments, the nerve ablation procedure is fordenervation of the renal artery. In another embodiment, the method isused for ensuring the accurate delivery of ablation energy to a targetednerve in the arterial wall during a nerve ablation process. In a furtherembodiment, the method is used for immediate post-procedural assessmentof the nerve ablation process to ensure that the targeted nerve has beenablated by the energy delivered in a nerve ablation procedure.

In certain embodiments, the energy is delivered to the arterial wall atdosage suitable for nerve stimulation. In other embodiments, the energyis delivered to the arterial wall at a dosage suitable for nerveablation.

In one embodiment, the physiological parameters comprise blood pressure,heart rate, biochemical levels, cardiac electrical activity, muscleactivity, skeletal nerve activity, action potential of cells or othermeasurable reactions as a result of these physiological changes such aspupil response, electromyogram and vascular constriction.

In some embodiments, an area on the arterial wall that, uponstimulation, causes increase in blood pressure and heart rate isconsidered as innervated with sympathetic nerves while, in contrary, anarea on the arterial wall that, upon stimulation, causes decrease inblood pressure and heart rate is considered as innervated withparasympathetic nerves.

In an embodiment, the energy for ablation is considered to be deliveredaccurately to a targeted nerve innervating the arterial wall when thephysiological parameters deviate significantly from the baseline duringthe ablation process.

In one embodiment, the nerve ablation procedure is considered to besuccessful when an area, confirmed to be innervated with nerves withsaid method before the delivery of ablation energy, no longer leads tochanges in the physiological parameters such as blood pressure and heartrate when stimulation energy is delivered to this spot.

The present invention also provides a system for locating andidentifying nerves innervating an arterial wall. The system comprisesone or more devices capable of delivering a dose of energy to anarterial wall; one or more sensors to receive signals of physiologicalparameters one or more devices for analysis of signals from the sensors;and one or more indicators or panels capable of displaying the resultsof the analysis

In one embodiment, the dose of energy delivered by the energy deliverydevice can be controlled to achieve either nerve stimulation or nerveablation. In another embodiment, two separate devices are used to carryout nerve stimulation and nerve ablation independently.

In another embodiment, the energy delivered is one or more ofelectrical, mechanical, ultrasonic, radiation, optical and thermalenergies.

In some embodiments, said sensors detect physiological parameters whichcomprise blood pressure, heart rate, biochemical levels, cardiacelectrical activity, muscle activity, skeletal nerve activity, actionpotential of cells and other measurable reactions as a result of theabove such as pupil response, electromyogram and vascular constriction.In certain embodiments, the signals corresponding to the physiologicalparameters are detected with commercially available technologies knownin the field.

In another embodiment, the device for digital analysis of thephysiological signals is a microcontroller or computer.

In one embodiment, the analyzed results are displayed using differentcolored indicators. An area innervated with sympathetic nerves isrepresented with a green indicator and an area innervated withparasympathetic nerves is represented with a red indicator. In anotherembodiment, the analyzed data are displayed on a digital viewing panel.

In one embodiment, the set of indicators or panels may be built intodevices in the system such as the energy delivery device. In certainembodiments, the set of indicators or panels may exist as a separateentity in the system.

The present invention also provides for specially-designed catheterswith a distal end (i.e. the catheter tip) in shapes customized to renalarchitecture, possessing one or more electrodes to map renal nervedistribution, to perform renal ablations, to perform post-ablationassessment and to perform angiography. In certain embodiments, theelectrodes of such catheters are sequentially spaced along the length ofthe catheter tip, where the electrode faces make contact with segmentedportions of the renal artery lumen. In certain embodiments, the tip ofthe catheter is steerable and has a single electrode for emitting radiofrequency energy. In certain embodiments, the shape of the catheter tipis a single helix wherein the coil of the helix is either round or flatin shape. In other embodiments, the catheter tip is a double helixwherein the coils of the helices are either round or flat in shape. Infurther embodiments, the catheter tip may comprise a balloon aroundwhich is wrapped a helical coil, wherein spaced along the length of thehelical coil are electrodes; alternately, the catheter tip may comprisea balloon around which is an umbrella component encapsulating theballoon, and wherein spaced along the umbrella component are electrodes.In variations of both embodiments, the coil or umbrella component may beeither round or flat in shape; consequently the electrodes spaced alongthe length of the coil or umbrella may be round or flat in shape,depending upon the underlying shape of the coil or umbrella.

In further embodiments, the catheter tip may comprise an umbrella shapeor frame with a closed end, or umbrella with an open end.

In certain embodiments, the above catheter tips may be introduced intothe arterial architecture to perform the functions of a stent.

In one embodiment, the diameter of these catheter tips may vary from 0.5mm to 10 mm; the length of the catheter tips may vary from 20 mm to 80mm; the diameters of coil may vary from 3.0 mm to 7.5 mm; the distancesbetween each coil may vary from 4 mm to 6 mm; and the fully uncoiledlengths of the coils may vary from 31 mm to 471 mm.

The electrodes of the catheters may be activated independently of oneanother or can be activated in any combination to emit electricalstimulation or radiofrequency energy. The electrodes each have dualfunctions of delivering electrical stimulation or radiofrequency energy.Electrical stimulation is used to identify and map segments of renalartery lumen beneath which lie renal nerves of importance. Saididentification and mapping is accomplished through the monitoring of aphysiological response or responses to the applied electricalstimulation, such as changes in blood pressure response and heart rateor muscle sympathetic nerve activity (Schlaich et al., NEJM 2009), orrenal norepinephrine spillover (Ester et al. 2009, and Schlaich et al.,J Htn. 2009), wherein changes in physiological response indicate thepresence of an underlying sympathetic nerve distribution in the vicinityof the activated electrode. In another embodiment, individual electrodesof the catheters may be activated in physician operator-selectedcombinations in order to assess maximal physiological response, and theconsequent locations of underlying renal nerves. The electrodes of thecatheters are able to emit not just electrical current of sufficientstrength to stimulate renal nerve, but thermal energy such asradiofrequency energy to ablate underlying renal nerve tissue based onrenal nerve mapping results. In other embodiments, separate electrodesof the catheters can be selectively activated to emit ablative energysuch as high radiofrequency energy wherein the choice of the activatedelectrodes is based upon the results of the mapping of the nerves. Infurther embodiments, based on the mapping of the renal nerves, ablativetechniques using other types of ablative energy such as laser energy,high intensive focused ultrasound or cryoablative techniques can beutilized on renal artery walls to ablate the sympathetic renal nerves.

In certain embodiments, these catheters are interchangeably used withexisting radiofrequency generators which are presently utilized withexisting cardiac catheter systems.

In one embodiment, the aforementioned catheter systems may be utilizedwith any variety of acceptable catheter guidewire previously insertedinto the patient's body to guide the catheter tip to the desiredlocation. They may also be used with devices and other instruments thatmay be used to facilitate the passage of like devices within thecardiovascular and renal vascular systems, such as sheaths and dilators.When required, the aforementioned catheter systems may also be utilizedwith a puller wire to position the catheter tip.

The present invention also provides methods of using the cathetersdescribed herein to map renal nerve distribution, comprising the stepsof using electrical stimulation while monitoring changes inphysiological responses, such as blood pressure and heart rate, to maprenal nerve distribution and identify ablation spots within renalarteries for ideal denervation of renal nerves. These methods compriseactivating the independent electrodes of the described catheters to emitan electrical charge to stimulate the underlying renal nerve whilemonitoring physiological responses such as blood pressure and heartrate; the presence of changes in physiological response indicate thepresence of an underlying sympathetic nerve in the vicinity of theactivated electrode and a superior location for ablation. Anagglomeration of mapping data may take the form of a clinically usefulguide respecting renal nerve distribution to assist clinicians inperforming ablation.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a schematic of a system of the present invention for locatingand identifying functional nerves innervating the wall of an artery. Thesystem comprises device 101 for delivery of energy to the arterial wall;power source 102 for powering device 101; sensor 103 for detectingsignals of physiological parameters; device 104 for analyzing the datafrom sensor 103; and indicator 105 to display the results from device104.

FIG. 2 is a schematic diagram depicting the steps in an embodiment ofthe method to determine whether functioning sympathetic orparasympathetic nerves are in the vicinity of a dose of energy deliveredto the arterial wall. The graphs illustrate possible recordedphysiological signals.

FIG. 3A shows an elevational view of the distal portion (catheter tip)of a single helix ablation catheter according to one embodiment of thepresent invention wherein electrodes 301 are placed at 90° intervalsalong the helix length, wherein the helical coil 303 itself is round,and wherein “L” designates the length of the distal portion, “l”designates the length of one turn of a single coil, “d” designatesdiameter of catheter tip and “D” designates diameter of the helicalcoil.

FIG. 3B shows the distribution of electrodes 301 in a single completecoil in the helix of the ablation catheter shown in FIG. 3A.

FIG. 3C shows an end-on view of the distal portion of a single helixablation catheter according to the embodiment shown in FIG. 3A from thedelivery direction of the lead, displaying only the first turn of thecoil with electrodes 301.

FIG. 3D shows an elevational view of the distal portion of a singlehelix ablation catheter according to an embodiment of the presentinvention wherein electrodes 305 are placed at 120° intervals along thehelix length, and wherein the helical coil 307 itself is round.

FIG. 3E shows the distribution of electrodes 305 in a single completecoil in the helix of the ablation catheter shown in FIG. 3D.

FIG. 3F shows an end-on view of the distal portion of a single helixablation catheter according to the embodiment shown in FIG. 3D from thedelivery direction of the lead, displaying only the first turn of thecoil with electrodes 305.

FIG. 3G shows an elevational view of the distal portion of a singlehelix ablation catheter according to an embodiment of the presentinvention wherein electrodes 309 are placed at 90° intervals along thehelix length, and wherein the helical coil 311 itself is flattened.

FIG. 3H shows the distribution of electrodes 309 in a single completecoil in the helix of the ablation catheter shown in FIG. 3G.

FIG. 3I shows an elevational view of the distal portion of a singlehelix ablation catheter according to the embodiment of the presentinvention wherein electrodes 313 are placed at 120° intervals along thehelix length, and wherein the helical coil 315 itself is flattened.

FIG. 3J shows the distribution of electrodes 313 in a single completecoil in the helix of the ablation catheter shown in FIG. 3I.

FIG. 44 shows an elevational view of a distal portion of a double helixablation catheter according to an embodiment of the present inventionwherein electrodes 417 are placed at 90° intervals along the length ofeach separate helix, wherein the helical coils 419 are round, andwherein “L” designates the length of the distal portion, and “l”designates the length of one turn of each helical coil.

FIG. 4B shows an end-on view of the distal portion of a double-helixablation catheter according to the embodiment shown in FIG. 4A from thedelivery direction of the lead, displaying only the first turn of eachcoil with electrodes 417.

FIG. 4C shows an elevational view of a distal portion of a double helixablation catheter according to an embodiment of the present inventionwherein electrodes 421 are spaced at 120° intervals along the length ofeach separate helix, wherein the helical coils 423 are round, andwherein “L” designates the length of the distal portion, and “l”designates the length of one turn of each helical coil.

FIG. 4D shows an end-on view of the distal portion of a double-helixablation catheter according to the embodiment shown in FIG. 4C from thedelivery direction of the lead, displaying only the first turn of eachcoil with electrodes 421.

FIG. 4E shows an elevational view of the distal portion of a doublehelix ablation catheter according to an embodiment of the presentinvention wherein electrodes 425 are spaced at 90° intervals along thelength of each separate helix, and wherein the helical coils 427 areflat.

FIG. 4F shows an elevational view of the distal portion of a doublehelix ablation catheter according to an embodiment of the presentinvention wherein electrodes 429 are spaced at 120° intervals along thelength of each separate helix, and wherein the helical coils 431 areflat.

FIG. 5A shows an elevational view of a distal portion of a balloonablation catheter according to an embodiment of the present invention,wherein the balloon 533 is inflated, and wherein electrodes 535 areevenly spaced at intervals along a helical coil 537 which is round inshape and wrapped around the balloon.

FIG. 5B shows an elevational view of a distal portion of a balloonablation catheter according to an embodiment of the present inventionincorporating an umbrella-like component 539 encapsulating the balloon541, wherein the balloon is inflated, and wherein electrodes 543 arespaced at intervals along the umbrella encapsulating the balloon.

FIG. 6A shows an elevational view of a distal portion of an ablationcatheter according to an embodiment of the present inventionincorporating a closed-end umbrella like frame 645 wherein electrodes647 are spaced at intervals along the umbrella like frame.

FIG. 6B shows an end-on view of the distal portion of an ablationcatheter according to the embodiment like shown in FIG. 6A from thedelivery direction of the lead.

FIG. 6C shows an elevational view of a distal portion of an ablationcatheter according to an embodiment of the present inventionincorporating an open-end umbrella like frame 649 wherein electrodes 651are spaced at intervals along the umbrella frame.

FIG. 6D shows an end-on view of the distal portion of an ablationcatheter from the delivery direction of the lead.

FIG. 7A shows an elevational view of a distal portion of an ablationcatheter according to an embodiment of the present invention wherein asingle electrode 755 is located at a steerable catheter tip 753.

FIG. 7B shows an end-on view of the distal portion of an ablationcatheter according to the embodiment shown in FIG. 7A from the deliverydirection of the lead, displaying the electrode 755.

FIG. 8 shows the experimental setup for acute pig experiments used innerve mapping experiments.

FIG. 9A shows Maximal and Minimal Effects of Left Renal ArteryStimulation on Arterial Systolic Pressure (ASP). Shown is arterialsystolic pressure (ASP, as measured in mmHg) after an electricalstimulation in the left renal artery (LRA); baseline measures, as wellmaximal and minimal responses after the stimulation are shown.

FIG. 9B shows Maximal and Minimal Effects of Left Renal ArteryStimulation on Arterial Diastolic Pressure (ADP). Shown is arterialdiastolic pressure (ADP, as measured in mmHg) after an electricalstimulation in the left renal artery (LRA); baseline measures, as wellas maximal and minimal responses after the stimulation are shown.

FIG. 9C shows Maximal and Minimal Effects of Left Renal ArteryStimulation on Mean Arterial Pressure (MAP). Shown is mean arterialpressure (MAP, as measured in mmHG) after an electrical stimulation inthe left renal artery (ERA); baseline measures, as well as maximal andminimal responses after the stimulation are shown.

FIG. 90 shows Maximal and Minimal Effects of Left Renal ArteryStimulation on Heart Rate (HR). Shown are maximal and minimal changes inheart rate after left renal artery (LRA) electrical stimulation;baseline measures, as well as maximal and minimal heart rates after thestimulation are shown.

FIG. 10A shows Maximal and Minimal Effects of Right Renal ArteryStimulation on Arterial Systolic Pressure (ASP), Shown is arterialsystolic pressure (ASP, as measured in mmHg) after stimulation in theright renal artery (RRA); baseline measures, as well maximal and minimalresponses after an electrical stimulation are shown.

FIG. 10B shows Maximal and Minimal Effects of Right Renal ArteryStimulation on Arterial Diastolic Pressure (ADP). Shown is arterialdiastolic pressure (ADP, as measured in mmHg) after an electricalstimulation in the right renal artery (RRA); baseline measures, as wellas maximal and minimal responses after the stimulation are shown.

FIG. 10C shows mean arterial pressure (MAP, as measured in mmHg) afteran electrical stimulation in the right renal artery (LRA); baselinemeasures, as well as maximal and minimal responses after the stimulationare shown.

FIG. 10D shows Maximal and Minimal Effects of Right Renal ArteryStimulation on Heart Rate (HR). Shown are maximal and minimal changes inheart rate after right renal artery (RRA) electrical stimulation;baseline measures, as well as maximal and minimal heart rates after thestimulation are shown.

FIG. 11 shows the decreases in heart rate once intra-renal arterystimulations were applied to certain locations of renal artery.

FIG. 12A shows Changes in Arterial Systolic Pressure (ASP) during FourSeparated Renal Ablation in Left Renal Artery. Shown are the changes inarterial systolic pressure (ASP, as measured in mmHg) during fourseparate renal ablations in the left renal artery (LRA).

FIG. 128 shows Changes in Arterial Diastolic Pressure (ADP) during FourSeparated Renal Ablation in Left Renal Artery. Shown are changes inarterial diastolic pressure (ADP, as measured in mmHg) during fourseparate renal ablations in the left renal artery (LRA).

FIG. 12C shows Changes in Mean Arterial Pressure (MAP) during FourSeparated Renal Ablation in Left Renal Artery. Shown are changes in meanarterial pressure (MAP, as measured in mmHg) during four separate renalablations in the left renal artery (LRA).

FIG. 12D shows Changes in Heart Rate (HR) during Four Separated RenalAblation in Left Renal Artery. Shown are changes in heart rate duringfour separate renal ablations in the left renal artery (LRA).

FIG. 13A shows Changes in Arterial Systolic Pressure (ASP) during FourSeparated. Renal Ablation in Right Renal Artery. Shown are changes inarterial systolic pressure (ASP, as measured in mmHg during fourseparate renal ablations in the right renal artery (RRA).

FIG. 13B shows Changes in Arterial Diastolic Pressure (ADP) during FourSeparated Renal Ablation in Right Renal Artery. Shown are changes inarterial diastolic pressure (ADP, as measured in mmHg) during fourseparate renal ablations in the right renal artery (RRA).

FIG. 13C Changes in Mean Arterial Pressure (MAP) during Four SeparatedRenal Ablation in Right Renal Artery. Shown are changes in mean arterialpressure (MAP, as measured in mmHg) during four separate renal ablationsin the right renal artery (RRA).

FIG. 13D shows Changes in Heart Rate (HR) during Four Separated RenalAblation in Right Renal Artery. Shown are changes in heart rate duringfour separate renal ablations in the right renal artery (RRA).

FIG. 14 shows the experimental setup for the chronic renal nerveablation experiments.

FIG. 15 shows histology map scheme for renal artery sections taken fromsacrificed animals.

DETAILED DESCRIPTION OF THE INVENTION

Please note that as referred to throughout this specification, the term“catheter” references the entire length of a catheter apparatus, fromthe distal portion intended for introduction into the desired targetanatomy for ablation or other action, extending through to the juncturewhere the catheter meets the cable linking the catheter to an RFgenerator. As referenced to through this specification, the term“catheter tip” is used to reference the distal portion of the catheterwhich carries electrodes, and performs stimulative, ablative, andmapping functions within the body at a targeted site of action. The term“catheter tip” is used interchangeably with terms referencing the“distal portion” of any recited catheter.

The renal nerve architecture is of paramount consideration beforesuccessful ablation can take place; therefore, individual renal nervearchitecture must be carefully considered or mapped beforecatheterization for denervation can be successfully accomplished. Thepresence of aberrant or unusual renal architecture, as well as normalvariation in renal nerve architecture among individuals require mappingof the renal nerves before ablation. In other words, mapping of therenal nerves is required before catheter denervation because the bestspots for ablation are “random” in the sense that the best spots forablation vary from one person to another, and from one artery toanother. Optimal ablation thus requires identification or mapping ofrenal nerves prior to catheter ablation.

This invention provides a system and method for locating sitesinnervated with functional nerves in the wall of arteries, particularlythe renal artery, though persons skilled in the art will appreciate thatnerves innervating other arteries or vessels in the human body may belocated using this invention. The system comprises one or more devicescapable of delivering a dose of energy to the wall of an artery; one ormore sensors to receive inputs of physiological signals; one or moredevices for analysis of signals from the sensors; and one or moreindicators or panels capable of displaying the results of the analysis.

FIG. 1 depicts an exemplary system in accordance with an aspect of theinvention, namely a renal denervation system using blood pressure andheart rate as the physiological parameters for identifying nerveresponse. The system comprises one or more of devices 101 for deliveryof energy to the arterial wall which is in electrical communication witha power source 102. System further comprises sensors 103 for detectingphysiological signals in electrical communication with device 104 foranalysis of the physiological signals. The indicator 105 in electricalcommunication with device 104 displays the result of the analysis fromdevice 104. Device 101, in the form of a dual-function catheter, isshown inserted into the renal artery via minimal invasive interventionalprocedure in this embodiment. At least one of the electrodes of device101 contacts the renal arterial wall at a defined location and iscapable of delivering a dose of energy from the power source 102 forstimulation or ablation of the nerves that may be innervating the areaof the arterial wall for which the electrode is in contact with. Sensors103 detect changes in blood pressure and/or heart rate as energysufficient for nerve stimulation or ablation is delivered from anelectrode on device 101 to the spot the electrode is contacting on thearterial wall. The signals from sensor 103 will be inputted to device104 which will determine digitally whether the signal elicited is due tosympathetic or parasympathetic nerves, or the lack thereof. Indicator105 will then display the result of the analysis from device 104.

In one embodiment of the invention, device 101 is an invasive deviceinserted into an artery capable of delivering energy to a nerveinnervating the artery, resulting in nerve stimulation or ablation. Inanother embodiment, device 101 is made up of two separate entities, onedelivering the energy for nerve stimulation, and the other nerveablation. In a different embodiment, device 101 is a single-electrodecatheter or multi-electrode catheter.

In one embodiment, power source 102 delivers energy to the arterial wallvia device 101. In another embodiment, energy is delivered remotelythrough the human body by power source 102 into the arterial wallwithout device 101. In a further embodiment, power source 102 is amulti-channel power source capable of delivering separate doses ofenergy independently to distinct locations on the arterial wall. Inother embodiments, power source 102 is a single channel power sourcecapable of delivering only 1 dose of energy each time. In anotherembodiment, the dosage of energy to be delivered by power source 102 isadjustable to induce different effects on a targeted nerve such asstimulation or ablation. In further embodiments, the energy delivered bypower source 102 is one or more of electrical, mechanical, ultrasonic,radiation, optical and thermal energies.

In one embodiment, sensors 103 detect signals from physiologicalparameters comprising blood pressure, heart rate, biochemical levels,cardiac electrical activity, muscle activity, skeletal nerve activity,action potential of cells and other measurable reactions as a result ofthe above such as pupil response, electromyogram and vascularconstriction. In a further embodiment, sensors 103 detect said signalsexternally with or without contacting any part of the human body. Inanother embodiment, sensors 103 detect said signals inside the humanbody by placing into contact with, or in the vicinity of, the lumen ofinterest such as the renal artery or femoral artery or any other artery.In yet another embodiment, sensor 103 could be a sensor from part ofanother equipment that is used in conjunction with this invention duringthe interventional procedure.

In an embodiment, device 104 is one or more microcontrollers orcomputers capable of digital analysis of the signals arising directly orindirectly from sensor 103.

In one embodiment, indicator 105 is one or more digital viewing panelsthat display the result from the analysis of device 104. In anotherembodiment, one or more results of said analysis from multiple locationson the arterial wall are simultaneously displayed on indicator 105. In afurther embodiment, indicator 105 also displays one or more thephysiological signals from sensor 103; energy related information frompower source 102 such as current, frequency, voltage; tissue-electrodeinterface related information such as impedance; and information relatedto device 101 such as temperature. In certain embodiments, indicator 105comprises a set of different colored lights each distinctly representingsympathetic nerve, parasympathetic nerve or no nerve. In otherembodiments, indicator 105 represents the result from analysis of device104 with texts, symbols, colors, sound or a combination of the above.

In certain embodiments, device 4 and indicator 5 are integrated as asingle device and, in further embodiments, both device 4 and indicator 5are integrated into power source 2.

In yet another embodiment, sensor 103, device 104 and indicator 105exist independently from device 101 and power source 102 such thatsensor 103, device 104 and indicator 105 can be used with other externalor invasive methods for energy delivery into the vessel wall such ashigh-intensity focused ultrasound.

The present invention additionally provides a method for identifying thepresence of functional sympathetic or parasympathetic nerves innervatinga selected area on the arterial wall based on changes in physiologicalparameters induced by a dose of energy. The method comprises one or moreof the steps of preparing a baseline of the physiological parameters tobe measured prior to the delivery of a dose of energy to the arterialwall; delivering a dose of energy to the arterial wall; detecting thephysiological changes as a result of the delivered energy; rating thechange based on a set of empirically pre-determined values: and, basedon the ratings, determining if there are functional sympathetic orparasympathetic nerves in the vicinity of the site of energy delivery.

FIG. 2 is a flow chart illustrating the steps of the method fordetermining the presence of any functional sympathetic orparasympathetic nerve innervating a selected area of an arterial wall.

At step 1, physiological signals from sensor 103 are continuouslyrecorded by device 104 to produce a reliable baseline reflective of anyinstantaneous changes in the signals.

Energy is then delivered by one of the electrodes in device 101 to thearea on the arterial wall that this electrode is in contact with (Step2). Sensor 103 detects any physiological change caused by the energydelivered, and the change is recorded as signals which are then sent todevice 104. (Step 3)

In step 4, device 104 determines the deviation of the physiologicalsignals from the baseline of step 1 and, in step 5, determines the typeof nerves innervating the area on the arterial wall based on thedeviation from the baseline information.

In one embodiment, the physiological signals detected by sensor 103comprises one or more of blood pressure, heart rate, biochemical levels,cardiac electrical activity, muscle activity, skeletal nerve activity,action potential of cells and other observable body reactions as aresult of the above such as pupil response and vascular constriction.

In an embodiment, the dosage of energy delivered in step 2 is adjustableto induce different interactions with a targeted nerve such as nervestimulation or nerve ablation.

In certain embodiments, the values of the physiological signals aremeasured using other external devices and inputted into device 104 priorto the energy delivery to replace the baseline formed by device 104.

In one embodiment, the changes in physiological parameters are detectedduring or after the energy delivery process in step 2. In anotherembodiment, the changes in physiological parameters are in the form ofnumerical values or waveforms. In further embodiments, the deviationfrom baseline of step 1 is evaluated by subtracting the baseline of step1 from the signals.

In one embodiment, the empirically pre-determined set of values could beobtained from sets of clinical data or deduced from the experience ofclinical physicians. In some embodiments, an area on the arterial wallis considered to be innervated with sympathetic nerves when energydelivered to the area causes an increase in heart rate by 10 beats perminute and/or an increase in blood pressure by 6 mmHg. In otherembodiments, an area on the arterial wall is considered to be innervatedwith parasympathetic nerves when energy delivered to the area causes adecrease in heart rate by 5 beats per minute and/or a decrease in bloodpressure by 2 mmHg.

In a further embodiment, the results of step 5 will be displayed onindicator 105.

In one embodiment, the method is used for identifying the suitable sitesfor nerve ablation in the arterial wall to disrupt baroreflex viasympathetic and parasympathetic nervous systems, in another embodiment,the method provides indication of whether the ablation energy isdelivered accurately to the targeted nerves in the arterial wall. In afurther embodiment, the method is used for immediate post-proceduralassessment of nerve ablation.

The present invention also provides for specially-designed catheterswith a steerable distal end (i.e. the catheter tip) in shapes customizedto renal architecture, possessing one or more electrodes to map renalnerve distribution, to perform renal ablations and to performangiography. In certain embodiments, the electrodes of such cathetersare sequentially spaced along the length of the catheter tip, where theelectrode faces make contact with segmented portions of the renal arterylumen. In certain embodiments, the shape of the catheter tip is a singlehelix wherein the coil of the helix is either round or flat in shape(FIGS. 3A-J). In other embodiments, the catheter tip is a double helixwherein the coils of the helices are either round or flat in shape(FIGS. 4A-F). In further embodiments, the catheter tip may comprise aballoon around which is wrapped a helical coil, wherein spaced along thelength of the helical coil are electrodes (FIG. 5A); alternately, thecatheter tip may comprise a balloon around which is an umbrellacomponent encapsulating the balloon, and wherein spaced along theumbrella component are electrodes (FIG. 5B). In variations of bothembodiments shown in FIGS. 5A and 5B, the coil or umbrella component maybe either round or flat in shape; consequently the electrodes spacedalong the length of the coil or umbrella may be round or flat in shape,depending upon the underlying shape of the coil or umbrella.

In further embodiments, the catheter tip may comprise an umbrella shapeor frame with a closed end (FIGS. 6A-B), or umbrella with an open end(FIG. 6C-D).

In another embodiment, the catheter has a steerable catheter tip with asingle electrode at its tip (FIG. 7A-B).

In certain embodiments, the above catheter tips may be introduced intothe arterial architecture to perform the functions of a stent.

In one embodiment, the diameter of these catheter tips, d, may vary from0.5 mm to 10 mm; the length of the catheter tips, L, may vary from 20 mmto 80 mm; the diameters of coil, D, may vary from 3.0 mm to 7.5 mm; thedistances between each coil, l, may vary from 4 mm to 6 mm; the numbersof coils may vary from 3.3 to 20; and the fully uncoiled lengths of thecoils may vary from 31 mm to 471 mm.

The electrodes of the catheters may be activated independently of oneanother or can be activated in any combination to emit electricalstimulation or radiofrequency energy. The electrodes each have dualfunctions of delivering electrical stimulation or radiofrequency energy.Electrical stimulation is used to identify and map segments of renalartery lumen beneath which lie renal nerves of importance. Saididentification and mapping is accomplished through the monitoring of aphysiological response or responses to the applied electricalstimulation, such as changes in blood pressure response and heart rateor muscle sympathetic nerve activity (Schlaich et al., NEJM 2009), orrenal norepinephrine spillover (Ester et al. 2009, and Schlaich et al.,J Htn. 2009), wherein changes in physiological response indicate thepresence of an underlying sympathetic nerve distribution in the vicinityof the activated electrode. In another embodiment, individual electrodesof the catheters may be activated in physician operator-selectedcombinations in order to assess maximal physiological response, and theconsequent locations of underlying renal nerves. The electrodes of thecatheters are able to emit not just electrical current of sufficientstrength to stimulate renal nerve, but thermal energy such asradiofrequency energy to ablate underlying renal nerve tissue based onrenal nerve mapping results. In other embodiments, separate electrodesof the catheters can be selectively activated to emit ablative energysuch as high radiofrequency energy wherein the choice of the activatedelectrodes is based upon the results of the mapping of the nerves. Infurther embodiments, based on the mapping of the renal nerves, ablativetechniques using other types of ablative energy such as laser energy,high intensive focused ultrasound or cryoablative techniques can beutilized on renal artery walls to ablate the sympathetic renal nerves.

In certain embodiments, these catheters are interchangeably used withexisting radiofrequency generators which are presently utilized withexisting cardiac catheter systems.

In one embodiment, the aforementioned catheter systems may be utilizedwith any variety of acceptable catheter guidewire previously insertedinto the patient's body to guide the catheter tip to the desiredlocation. They may also be used with devices and other instruments thatmay be used to facilitate the passage of like devices within thecardiovascular and renal vascular systems, such as sheaths and dilators.When required, the aforementioned catheter systems may also be utilizedwith a puller wire to position the catheter tip.

The present invention also provides methods of using the cathetersdescribed herein to map renal nerve distribution, comprising the stepsof using electrical stimulation while monitoring changes inphysiological responses, such as blood pressure and heart rate, to maprenal nerve distribution and identify ablation spots within renalarteries for ideal denervation of renal nerves. These methods compriseactivating the independent electrodes of the described catheters to emitan electrical charge to stimulate the underlying renal nerve whilemonitoring physiological responses such as blood pressure and heartrate: the presence of changes in physiological response indicate thepresence of an underlying sympathetic nerve in the vicinity of theactivated electrode and a superior location for ablation. Anagglomeration of mapping data may take the form of a clinically usefulguide respecting renal nerve distribution to assist clinicians inperforming ablation.

In one embodiment, the tip of said catheter is optionally moved in ablood vessel according to a specified protocol in order to make contactwith desired portions of the renal artery lumen. In one embodiment, theoptional protocol for moving the catheter tip in the above methodcomprises moving the stimulator or ablative section of the catheter tipfrom the half of the renal artery closer to the interior of the kidneyto the half of the renal artery closer to the aorta and applying one ormore electrical stimulation to each of the two halves.

In another embodiment, the optional protocol for moving the catheter tipcomprises turning the stimulatory or ablative section of the cathetertip within the renal artery in the following sequence: (a) turning fromthe anterior wall to the posterior wall of the artery; (b) turning fromthe posterior wall to the superior wall of the artery; and (c) turningfrom the superior wall to the interior wall of the artery, wherein eachturn is 90° or less. In one embodiment, one or more electricalstimulations are applied after each turning of the catheter tip withinthe renal artery.

In one embodiment, the electrical stimulation applied falls within thefollowing parameters: (a) voltage of between 2 to 30 volts; (b)resistance of between 100 to 1000 ohms; (c) current of between 5 to 40milliamperes; (d) applied between 0.1 to 20 milliseconds.

The present invention also provides a method of ablating renal nerves totreat disease caused by systemic renal nerve hyperactivity, comprisingthe steps of: (a) applying the mapping method described herein to maprenal nerves; (h) applying radiofrequency energy through the catheter tosite-specific portions of the renal artery lumen to ablate the mappedrenal nerves; and (c) applying stimulation again to assess theeffectiveness of ablation. In further embodiments, based on the mappingof the renal nerves, other ablative techniques generally known in theart can be utilized on renal artery walls to ablate the sympatheticrenal nerves, e.g. ablative techniques using other ablative energy suchas laser energy, high intensive focused ultrasound or cryoablativetechniques.

The present invention provides for a catheter adapted to be used in amethod for locating or identifying a functional nerve innervating thewall of a blood vessel in a subject, comprising a shaft, wherein theproximal end of said shaft is configured to be connected to an energysource, and the distal end (catheter tip) of said shaft is in the formof a single helix, double helix or multiple prongs having one or moreelectrodes.

In one embodiment, said catheter comprises one or more electrodes thatare configured to emit energy sufficient to stimulate or ablate a nerveon said vessel. In a further embodiment, said electrodes may beactivated independently of one another.

In one embodiment, said catheter is between 1 and 2 m in length, whereinthe catheter tip is between 2 and 8 CM in length, and between 0.5 mm and10 mm in diameter.

In one embodiment, said catheter contains helical coils or prongs whichare substantially round or flat in shape, and the electrodes are spacedalong the length of said coils or prongs, wherein said electrodes areembedded in said coils or prongs, or lie on the surface of said coils orprongs. In one embodiment, the prongs are rejoined at the distal end. Inyet another embodiment, the electrodes are evenly spaced along thelength of said coils at 90° or 120° from each other.

In one embodiment, said catheter has a catheter tip that is configuredto hold a balloon inflatable to fill the space within the coil of saidhelix or prongs.

The present invention also provides a method of using a catheter tolocate or identify a functional nerve innervating the wall of a bloodvessel in a subject, comprising the steps of: a) inserting said catheterinto said blood vessel and activating the electrodes on the catheter todeliver energy to one or more locations on said vessel wall sufficientto change one or more physiological parameters associated with theinnervation of said vessel by a sympathetic or parasympathetic nerve;and b) measuring said one or more physiological parameters after eachenergy delivery, and determining the change from the correspondingparameters obtained without energy delivery to said vessel; wherein alack of change in said physiological parameters in step h indicates theabsence of a functional nerve at the location of energy delivery, asignificant change in said physiological parameters in step b indicatesthe presence of a functional nerve at the location of energy delivery;and the direction of change in said physiological parameters in step bdetermines the nerve to be sympathetic or parasympathetic at thelocation of energy delivery. It is to be understood that a lack ofchange means that the change would be considered by someone skilled inthe art to be negligible or statistically insignificant, and asignificant change means that the change would be considered by someoneskilled in the art to be meaningful or statistically significant.

In one embodiment, said vessel is an artery; including a renal artery.In one embodiment, the functional nerve is related to baroreflex. In oneembodiment, the location where energy is delivered is an area where anerve has been ablated, wherein a lack of change in said physiologicalparameters in step b confirms nerve ablation. In another embodiment, thesubject used is a human or non-human animal. In another embodiment, thephysiological parameters described are selected from blood pressure,heart rate, cardiac electrical activity, muscle activity, skeletal nerveactivity, action potential of cells, pupil response, electromyogram,vascular constriction, and levels of biochemicals selected fromepinephrine, norepinephrine, renin-angiotensin II and vasopressin. Inyet another embodiment, said energy is adjustable and consists of one ormore of electrical, mechanical, ultrasonic, radiation, optical andthermal energies. In one embodiment, said energy causes nervestimulation or nerve ablation. In another embodiment; the functionalnerve is a sympathetic or parasympathetic nerve. In yet anotherembodiment, the energy delivered falls within the following ranges: a)voltage of between 2 and 30 volts; b) resistance of between 100 and 1000ohms; c) current of between 5 and 40 milliamperes; and d) time ofapplication between 0.1 and 20 milliseconds.

In one embodiment, the catheter used for insertion into a blood vesselis moved in the blood vessel in the following sequence: a) turning 90°or less from the anterior wall to the posterior wall of the artery; g)turning 90° or less from the posterior wall to the superior wall of theartery; and c) turning 90° or less from the superior wall to theinferior wall of the artery.

It will be appreciated by persons skilled in the art that the system andmethod disclosed herein may be used in nerve ablation of the renalartery to disrupt baroreflex via sympathetic and parasympathetic nervoussystems but its application could be extended to any innervated vesselsin the body.

The invention will be better understood by reference to the ExperimentalDetails which follow, but those skilled in the art will readilyappreciate that the specific examples are for illustrative purposes onlyand should not limit the scope of the invention which is defined by theclaims which follow thereafter.

It is to be noted that the transitional term “comprising”, which issynonymous with “including”, “containing” or “characterized by”, isinclusive or open-ended and does not exclude additional, un-recitedelements or method steps.

Example 1 Locating Nerves Innervating an Arterial Wall

A method to locate nerves innervating an arterial wall via examinationof the changes in physiological parameters after the delivery of asuitable dose of energy was designed and executed in acute pigexperiments. The aims of this experiments are:

-   1. To test currently existing cardiac ablation catheters (7F,B-Type,    spacing 2-5-2 mm, CELSIUS® RMT Diagnostic/Ablation Steerable    Catheter, Biosense Webster, Diamond Bar, Calif. 91765, USA) and a    radiofrequency generator (STOCKERT 70 RF Generator, Model Stockert    GmbH EP-SHUTTLE ST-3205, STOCKERT GmbH, Freiburg, Germany) for the    purposes of renal nerve mapping and ablation.-   2. To test renal nerve mapping via examination of changes in blood    pressure and heart rate during emission of electrical stimulation at    different sites within the lumen of the left and right renal    arteries.-   3. To determine the safe range of high radiofrequency energy to be    emitted to renal arteries for renal nerve ablation via examination    of visual changes of renal arterial walls and histology.-   4. To use changes in blood pressure and heart rate as indices of    efficient ablation of renal nerves during renal ablation.

Three pigs (body weight from 50-52 kg) were anesthetized withintravenous injection of sodium pentobarbital at 15 mg/kg. Thephysiological parameters: systolic blood pressure, diastolic bloodpressure, mean arterial pressure and heart rate were monitored. Theexperimental design and protocol are illustrated FIG. 8.

The ablation catheter used in this set of experiments was the 7F,B-Type,spacing 2-5-2 mm, CELSIUS® RMT Diagnostic/Ablation Steerable Catheter(Biosense Webster, Diamond Bar, Calif. 91765, USA) and a Celsiusradiofrequency generator (STOCKERT 70 RF Generator, Model Stockert GmbHEP-SHUTTLE ST-3205, STOCKERT GmbH, Freiburg, Germany).

Baselines for systolic, diastolic and mean arterial blood pressure andheart rate were measured before the delivery of electrical energy todifferent areas of the renal arterial wall. Mean arterial blood pressureand heart rate were then measured 5 seconds to 2 minutes after thedelivery of energy to note for any effects. By recognizing that asignificant change in blood pressure and heart rate to be associatedwith nerve stimulation, it was found that, although the segment of thearterial wall that is innervated varies in each animal, the methoddescribed herein has correctly located these areas in each of theanimals giving a map of the innervated regions in the renal artery.

Example 2 Relationship Between Physiological Parameters and the NervesInnervating an Arterial Wall

In order to demonstrate that energy delivered to different locations onan arterial wall may result in different effects on physiologicalparameters such as blood pressure and heart rate, and suchcharacteristics can be capitalized on to identify the type of nerveinnervating an arterial wall, electrical energy was delivered to theinnervated areas on the renal arterial walls of the pig model accordingto several strategies. Detailed parameters on the electrical energydelivered to Pig #1, Pig #2 and Pig #3 are shown in Table 1, Table 2 andTable 3 respectively.

In Pig #1, four separate stimulations took place in the left renalartery and two separate stimulations were performed in the right renalartery. As preliminary approaches, on the abdominal side of the leftrenal artery, two separate doses of electrical energy were delivered:one to the anterior wall and one to the posterior wall of the artery. Onthe kidney side of the left renal artery, two separate doses ofelectrical enemy were delivered: one to the anterior wall and one to theposterior wall of the artery. Different effects of these energies onblood pressure and heart rate were observed. In the right renal artery,one dose of electrical energy was delivered to the renal artery on theabdominal side and the kidney side, respectively. The same stimulationstrategy was used for Pig #2 and Pia #3.

The electrical energy delivered to different locations in the renalartery caused different effects on the systolic blood pressure,diastolic blood pressure, mean blood pressure and heart rate in all ofthe pigs tested. For instance; in response to the electrical energydelivered to the left kidney, the maximal change in systolic bloodpressure was respectively 19.5 mmHg and 29 mmHg in Pig #1 and Pia #3;the minimal change of systolic blood pressure was respectively 2 mmHgand 1 mmHg in Pig #1 and Pig #3, However, in Pig #2, changes in systolicblood pressure were consistent when the electrical energy was deliveredto either the abdominal aorta side or the kidney side. Furthermore, thestimulation location which caused the maximal effect or minimal effectvaried from animal to animal, indicating that the distribution of renalautonomic nerves is not consistent between animals. These phenomena insystolic blood pressure, diastolic blood pressure, mean arterial bloodpressure and heart rate during delivery of electrical energy to wall ofthe left renal artery were observed and further summarized in Table 4A,4B, 4C and 4D, respectively. Similar phenomenon in systolic bloodpressure, diastolic blood pressure, mean arterial blood pressure andheart rate during electrical stimulation in the right renal artery werealso observed and further summarized in Table 5A, 5B, 5C and 5D,respectively.

These data provide proof of concept for locating and identifying nervesinnervating an arterial wall specifically, that a substantialphysiological response, in this case, the maximal increase or decreasein measured blood pressure, was induced by delivery of electrical energyvia a catheter placed at a defined location where renal nerve branchesare abundantly distributed. Averaged data (mean±SD) calculated fromTable 4A-D and Table 5A-D are graphically represented in FIG. 9 and FIG.10, inclusive of all sub-figures.

TABLE 1 Renal Nerve Stimulation for Mapping Pig #1: Renal ArteryStimulation Site Stimulation Parameters Left Kidney side Anterior Wall15 V; 0.4 ms; 400 Ohm; 17 mA Posterior Wall 15 V; 0.4 ms; 400 Ohm; 28 mAAbdominal Anterior Wall 15 V; 0.2 ms; 400 Ohm; 28 mA Aorta SidePosterior Wall 15 V; 0.2 ms; 540 Ohm; 28 mA Right Kidney side 15 V; 0.2ms; 600 Ohm; 25 mA Abdominal Aorta Side 15 V; 0.2 ms; 520 Ohm; 25 mA

TABLE 2 Renal Nerve Stimulation for Mapping Pig #2: Renal ArteryStimulation Site Stimulation Parameters Left Kidney side 15 V; 0.2 ms;580 Ohm; 26 mA Abdominal Aorta Side 15 V; 0.2 ms; 480 Ohm; 28 mA RightKidney side 15 V; 0.2 ms; 520 Ohm; 28 mA Abdominal Aorta Side 15 V; 0.2ms; 500 Ohm; 28 mA

TABLE 3 Renal Nerve Stimulation for Mapping Pig #3: Renal ArteryStimulation Site Stimulation Parameters Left Kidney side 15 V; 9.9 ms;800 Ohm; 28 mA Abdominal Aorta Side 15 V; 9.9 ms; 800 Ohm; 28 mA RightKidney side 15 V; 9.9 ms; 800 Ohm; 28 mA Abdominal Aorta Side 15 V; 9.9ms; 800 Ohm; 28 mA

TABLE 4A Changes in Systolic Blood Pressure (SBP) During ElectricalStimulation in Left Renal Artery Left Renal Stimulation SBP MaximalResponses (mmHg) Minimal Responses (mmHg) Ani- Stimula- Stimula- malBase- Max- tion Base- Min- tion No. line imal Δ Location line imal ΔLocation Pig 1 131.5 151 19.5 AO Side 140 142 2 Renal Side Pig 2 155 1594 Renal Side 155 159 4 AO Side Pig 3 173 202 29 Renal Side 169 170 1 AOSide Aver- 153.2 170.7 17.5 154.7 157.0 2.3 age SD 20.8 27.4 12.6 14.514.1 1.5

TABLE 4B Changes in Diastolic Blood Pressure (DBP) During ElectricalStimulation in Left Renal Artery Left Renal Stimulation DBP MaximalResponses (mmHg) Minimal Responses (mmHg) Ani- Stimula- Stimula- malBase- Max- tion Base- Min- tion No. line imal Δ Location line imal ΔLocation Pig 1 99 108 9 AO Side 116 117 1 Renal Side Pig 2 112 115 3Renal Side 114 116 2 AO Side Pig 3 119 139 20 Renal Side 110 115 5 AOSide Aver- 110.0 120.7 10.7 113.3 116.0 2.7 age SD 10.1 16.3 8.6 3.1 1.02.1

TABLE 4C Changes in Mean Arterial Pressure (MAP) During ElectricalStimulation in Left Renal Artery Left Renal Stimulation MAP MaximalResponses (mmHg) Minimal Responses (mmHg) Ani- Stimula- Stimula- malBase- Max- tion Base- Min- tion No. line imal Δ Location line imal ΔLocation Pig 1 112.5 125 12.5 AO Side 123 128 5 Renal Side Pig 2 130 1333 Renal Side 131 132 1 AO Side Pig 3 141 158 17 Renal Side 136 138 2 AOSide Aver- 127.8 138.7 10.8 130.0 132.7 2.7 age SD 14.4 17.2 7.1 6.6 5.02.1

TABLE 4D Changes in Heart Rate (HR) During Electrical Stimulation inLeft Renal Artery Left Renal Stimulation HR Maximal Responses(beats/min) Minimal Responses (beats/min) Ani- Stimula- Stimula- malBase- Max- tion Base- Min- tion No. line imal Δ Location line imal ΔLocation Pig 1 150 151 1 Renal Side 140 130 −10 Renal Side Pig 2 126 1326 AO Side 132 120 −12 Renal Side Pig 3 138 142 4 Renal Side 159 150 −9AO Side Aver- 138.0 141.7 3.7 143.7 133.3 −10.3 age SD 12.0 9.5 2.5 13.915.3 1.5

TABLE 5A Changes in Systolic Blood Pressure (SBP) During ElectricalStimulation in Right Renal Artery Right Renal Stimulation SBP MaximalResponses (mmHg) Minimal Responses (mmHg) Ani- Stimula- Stimula- malBase- Max- tion Base- Min- tion No. line imal Δ Location line imal ΔLocation Pig 1 151.5 156 4.5 Renal Side 155 158 3 AO Side Pig 2 153 16613 Renal Side 157 162 5 AO Side Pig 3 154 167 13 Renal Side 157 162 5 AOSide Aver- 152.8 163.0 10.2 156.3 160.7 4.3 age SD 1.3 6.1 4.9 1.2 2.31.2

TABLE 5B Changes in Diastolic Blood Pressure (DBP) During ElectricalStimulation in Right Renal Artery Right Renal Stimulation DPB MaximalResponses (mmHg) Minimal Responses (mmHg) Ani- Stimula- Stimula- malBase- Max- tion Base- Min- tion No. line imal Δ Location line imal ΔLocation Pig 1 111.5 113 1.5 Renal Side 113 113 0 AO Side Pig 2 113 1196 Renal Side 114 117 3 AO Side Pig 3 110 113 3 Renal Side 112 110 −2 AOSide Aver- 111.5 115.0 3.5 113.0 113.3 0.3 age SD 1.5 3.5 2.3 1.0 3.52.5

TABLE 5C Changes in Mean Arterial Pressure (MAP) During ElectricalStimulation in Right Renal Artery Right Renal Stimulation MAP MaximalResponses (mmHg) Minimal Responses (mmHg) Ani- Stimula- Stimula- malBase- Max- tion Base- Min- tion No. line imal Δ Location line imal ΔLocation Pig 1 130 130 0 AO Side 131 130 −1 Renal Side Pig 2 130 141 11Renal Side 132 135 1 AO Side Pig 3 127 130 3 Renal Side 130 131 1 AOSide Aver- 129.0 133.7 4.7 131.0 132.0 1.0 age SD 1.7 6.4 5.7 1.0 2.62.0

TABLE 5D Changes in Heart Rate (HR) During Electrical Stimulation inRight Renal Artery Right Renal Stimulation HR Maximal Responses(beats/min) Minimal Responses (beats/min) Ani- Stimula- Stimula- malBase- Max- tion Base- Min- tion No. line imal Δ Location line imal ΔLocation Pig 1 141 146 5 AO Side 144 135 −9 Renal Side Pig 2 135 147 12Renal Side 120 117 −3 AO Side Pig 3 129 135 6 Renal Side 126 123 −3 AOSide Aver- 135.0 142.7 7.7 130.0 125.0 −5.0 age SD 6.0 6.7 3.8 12.5 9.23.5

TABLE 6 Possible effects of stimulating renal nerves Change of bloodChange of heart Animal pressure when renal rate when renal PublicationModel nerve stimulated nerve stimulated Ueda H, Uchida Y and Kamisaka K,Dog decrease N/A “Mechanism of the Reflex Depressor Effect by Kidney inDog”, Jpn. Heart J., 1967, 8 (6): 597-606 Beacham W S and Kunze D L, Catdecrease N/A “Renal Receptors Evoking a Spinal Vasometer Reflex”, J.Physiol., 1969, 201 (1): 73-85 Aars H and Akre S Rabbit decrease N/A“Reflex Changes in Sympathetic Activity and Arterial Blood PressureEvoked by Afferent Stimulation of the Renal Nerve”, Acta Physiol.Scand., 1970, 78 (2): 184- 188 Ma G and Ho S Y, Rabbit decrease Decrease“Hemodynamic Effects of Renal Interoreceptor and Afferent NerveStimulation in Rabbit”, Acta Physiol. Sinica, 1990, 42 (3): 262- 268 LuM, Wei S G and Chai X S, Rabbit decrease Decrease “Effect of ElectricalStimulation of Afferent Renal Nerve on Arterial Blood Pressure, HeartRate and Vasopressin in Rabbits”, Acta Physiol. Sinica, 1995, 47 (5):471-477

Among all the stimulation experiments performed in pigs according to thepreviously described protocol, certain locations in the renal arterialwall led to significant decreases in heart rate without causing changesin the blood pressure or the change in blood pressure is minimal incomparison to the decrease in heart rate (FIG. 11). Slight decreases inblood pressure, especially, diastolic blood pressure were oftenrecorded. Out of the 56 data points inclusive of all 4 physiologicalparameters evaluated in the experiments, there were at least 1 datapoint from each physiological parameter that responded with the dose ofenergy by a drop or no/insignificant change in value; this accounted forover 23% of the data points in this experiment. These distinctivephysiological changes in response to the stimulations appear to indicatethat nerves innervating these locations are of parasympathetic natureand are different from those sympathetic nerves innervating thelocations that results in increases in blood pressure and heart rateupon stimulation. Table 6 summarized the effect of delivering a suitabledose of energy to the afferent renal nerve in different studiesinvolving animal models of dogs, cats and rabbits. In conjunction withthis invention, the studies in Table 6 had demonstrated that it is notuncommon to induce effects akin to parasympathetic activity when asuitable dose of energy is delivered to the nerves innervating thekidney. In other words, there is an indication that, in the neuralcircuitry of the renal artery, there exist nerves that can induceparasympathetic activity rather than sympathetic activity and thereforeshould not be ablated when treating blood pressure related diseases.

Example 3 Ensuring Energy is Directed to a Target Nerve During Ablation

Subsequent to the studies for locating and identifying nerves in anarterial wall, energies at dosage suitable for ablations were alsodelivered to the innervated spots in the renal arterial wall of the samepigs. Four ablations were each delivered to the left and to the rightrenal arteries starting from the kidney side and moving to the abdominalaorta side in the order of movement from the anterior, to the posterior,to the superior and then to the inferior wall; each ablation was ≤5 minapart from the location of the previous ablation and the electrode head(catheter tip) of the ablation catheter was turned 90 degrees after eachablation. Based on the literature (Krum 2009, 2010) low energy level(5-8 watts) should be used for renal ablation; therefore, 5 watts and 8watts were used for renal ablation. For left renal artery ablation, theenergy level applied was 5 watts and the time length of ablation was 120seconds; for the right renal artery, the ablation energy level appliedwas 8 watts and the time length was 120 seconds. The temperature at theablation site was measured to be from 40° C. to 50° C. The physiologicalparameters: systolic blood pressure, diastolic blood pressure, meanarterial pressure and heart rate were examined during ablations. Thedata clearly showed that ablation at different locations within therenal artery resulted in differing changes in blood pressure and heartrate, further demonstrating that changes in physiological parameterssuch as blood pressure and heart rate can be used as indicators for anaccurate delivery of ablation energy to a targeted nerve and providedfurther evidence that distribution of the nerves in the arterial wallvaried case by case.

Changes in systolic blood pressure, diastolic blood pressure, meanarterial pressure and heart rate during four separate renal ablations inthe renal arteries of the left kidney were summarized in FIGS. 12A, 125,12C and 12D, respectively. Changes in arterial systolic and diastolicpressure, mean arterial pressure and heart rate during four separaterenal ablations in the renal arteries of the right kidney weresummarized in FIGS. 13A, 1311, 13C and 13D, respectively.

Example 4 Chronic Renal Nerve Ablation Experimental Results

This set of experiments involves methods to determine the safety profileof the energy levels used in existing cardiac ablation catheters in thedenervation of renal nerves. FIG. 14 describes the details of thisexperiment.

The ablation catheter used in this set of experiments was the 7F,B-Type,spacing 2-5-2 min, CELSIUS® RMT Diagnostic/Ablation Steerable Catheter(Biosense Webster, Diamond Bar, Calif. 91765, USA) and a Celsiusradiofrequency generator (STOCKERT 70 RF Generator, Model Stockert GmbHEP-SHUTTLE ST-3205, STOCKERT GmbH; Freiburg, Germany), Four pigs wereused in the study.

The energy levels used for the ablations applied were as follows: RightRenal Artery Ablation, 8 W, 120 s; Left Renal Artery Ablation 16 W, 120s (n=3). Right Renal Artery Ablation, 16 W, 120 s; Left Renal ArteryAblation, 8 W, 120 s (n=3).

The pigs were anesthetized, and 4-5 renal ablations were performed foreach renal artery (right and left) separately. Renal angiography wasperformed before and after the ablation to examine the patency of renalarteries. Pigs were allowed to recover from the procedures. In order todetermine the safety levels of ablation energy, one pig (Right renalartery. 16 W, 120 s; Left renal artery ablation, 8 W, 120 s) wasterminated for assessment of acute lesions due to two different energylevels of ablation. Twelve weeks after the ablation procedure,angiography was performed on the animals for both renal arteries.Thereafter, the animals were sacrificed, and renal arteries and kidneysexamined for any visible abnormalities; pictures were taken with renalarteries intact and cut open, with both kidneys cut open longitudinally.Samples from both renal arteries were collected for further histologystudies according to the histology maps shown in FIG. 15.

Example 5 Renal Mapping Catheter Designs

New catheters designed with functions of stimulation, mapping; ablationand angiography are hereby disclosed.

The catheter apparatus comprises an elongated catheter having a cathetertip on the distal end which, once inserted, is intended to remain in astatic position within the renal vascular architecture; a proximal end;and a plurality of ablation electrodes. In one embodiment, the ablationelectrodes are evenly-spaced down the length of the elongated cathetertip. The plurality of these ablation electrodes are spaced from theproximal end and from the distal end of the elongated catheter tip byelectrically nonconductive segments. In one embodiment, the firstelectrode on the tip side of the catheter or on the end side of thecatheter can be used as a stimulation reference for any other electrodesto deliver electrical stimulation; alternatively, any one of theseelectrodes can be used as a reference for other electrodes.

In one embodiment, the elongated catheter tip is of a helical shape.

In another embodiment, one or more conducting wires are coupled with andsupplying direct or alternating electrical current to the plurality ofelectrodes via one or more conducting wires. A controller is configuredto control the electrical current to the plurality of electrodes ineither an independent manner, or a simultaneous manner while thecatheter tip remains in a static position in the renal artery.

In another embodiment, one or more conducting wires are coupled with andsupplying radiofrequency (RF) energy to the plurality of electrodes, theRE energy being either unipolar RE energy or bipolar RF energy. Aradiofrequency generator supplies energy via the one or more conductingwires to the plurality of electrodes. A controller is configured tocontrol the energy source to supply energy to the plurality ofelectrodes in either an independent manner, a sequential manner, or asimultaneous manner while the catheter tip remains in a static positionin the renal artery

The RE energy sent to the electrodes may be controlled so that onlylow-level electrical energy impulses are generated by the electrodes inorder to merely stimulate underlying nerve tissue, and in particular,renal nerve tissue. Alternately, the RE energy sent to the electrodesmay be controlled so that greater electrical energy impulses aregenerated by the electrodes in order to ablate underlying nerve tissue,and in particular, renal nerve tissue. The catheter tip, and inparticular, the electrodes, are designed to remain in contact with therenal artery lumen, in the same place, throughout stimulation andablation

in another embodiment, the catheter is capable of being used withradiofrequency generators currently utilized in the practice of cardiactissue ablation. These radiofrequency generators may include, but arenot necessarily limited to those currently produced by Medtronic,Cordis/Johnson & Johnson, St. Jude Medical, and Biotronic.

Exemplary embodiments of the invention, as described in greater detailbelow, provide apparatuses for renal nerve denervation

FIGS. 3 to 7 are examples and illustrations of these ablation catheterand electrodes. Shown are elevational, cross-sectional, and end-on viewsof a distal portion of the ablation catheter tip according to variousembodiments of the present invention.

In one embodiment, the catheter has an elongated tip of a helical shape,A plurality of electrodes is evenly spaced starting from their placementat the proximal end of the catheter tip through the distal end of thecatheter tip by electrically nonconductive segments.

In certain embodiments, the catheter tip of the ablation cathetercomprises a single helix; in others, it is composed of a double helix.The coil or coils of the helix or helices of the catheter tip may beeither round or flat. Electrodes may be placed evenly down the length ofthe coils; for example, they can be spaced either 60°, 90° or 120°apart, but may be placed in other conformations or separated bydifferent degrees

In one embodiment, the electrodes may be either flat and rectangular orsquare in shape, if the coil of a helix is itself flattened.Alternately, the electrodes may be round and/or built into the helix ifthe coil is itself round. In another embodiment, the catheter tip has alength of from 2.0 cm to 8.0 cm and a diameter of 0.5 mm to 10.0 mm; thediameters of coil may vary from 3.0 mm to 7.5 mm; the distances of eachcoil may vary from 4 mm to 6 mm; and the fully uncoiled lengths of thecoils may vary from 31 mm to 471 mm; the catheter's total length is from1 m to 2.0 m.

In another embodiment, the catheter tip of the ablation cathetercomprises a balloon catheter system. In one embodiment, electrodes areevenly spaced at intervals along a helical coil which is either round orflat in shape and wrapped around the balloon; in other embodiments,electrodes are spaced along an umbrella frame apparatus which is eitherround or flat in shape and wrapped down the length of the balloon. Incertain embodiments, the umbrella frame apparatus has an open end and inothers, a closed end. The electrodes will come into contact with therenal architecture upon inflation of the balloon apparatus. In oneembodiment, the catheter tip has a length of 2.0 cm to 8.0 cm and adiameter from 0.5 mm to 10.0 mm when the balloon is not inflated; thediameters of coil may vary from 3.0 mm to 8 mm; the distances of eachcoil may vary from 4 mm to 6 mm: the numbers of coils may vary from 3.3to 20; and the fully uncoiled lengths of the coils may vary from 31 mmto 471 mm. the catheter's total length is from 1 in to 2.0 m.

In one embodiment, the diameter of the catheter tip when the balloon isinflated may range from 0.5 mm to 10 mm. The diameter of the coil aroundthe balloon may range from 3 mm to 10 mm and the diameter of a fullyinflated balloon is from 3 mm to 10 mm.

The invention may also comprise a catheter tip which is tube-like,cylindrical, and self-expanding with adjustable sizes. The materialsused for these catheter tips may, in certain embodiments, comprisenickel-titanium (nitinol) alloy.

In one embodiment of this invention, there is provided a renal nervemodulation and ablation processes (on either the left side kidney, rightside kidney, or both) comprising insertion of one of the cathetersdescribed above into either the left renal artery (LRA) or the rightrenal artery (RRA) followed by renal nerve mapping as substantiallydescribed above, followed by targeted ablation by individual electrodes.

In one embodiment, nerve stimulation takes place by application of thefollowing parameters: 0.1 ms-20 ms, 2V-30V, 5 mA-40 mA, and 100 Ohm-1000Ohm. In one embodiment, nerve ablation takes place by application of thefollowing parameters: below 12 watts and 30 seconds-180 seconds.

REFERENCES

-   1. Aars, H. and Akre, S., (1970), Reflex Changes in Sympathetic    Activity and Arterial Blood Pressure Evoked by Afferent Stimulation    of the Renal Nerve, Acta Physiol. Scand., 78 (2): 184-188-   2. Beacham, W. S. and Kunze, D. L., (1969), Renal Receptors Evoking    a Spinal Vasometer Reflex, J. Physiol., 201 (1): 73-85-   3. Campese, V. M., Kogosov, E., (April 1995), Renal afferent    denervation prevents hypertension in rats with chronic renal    failure, 25(4 Pt. 2): 878-882.-   4. Campese, V. M., and Krol, E., (June 2002), Neurogenic factors in    renal hypertension, Current Hypertension Reports, 4(3):256-260.-   5. Converse, R. L. Jr., Jacobsen, T. N., Toto, R. D., Jost, C. M.,    Cosentino, F., Fouad-Tarazi, F., Victor, R. G., (December 1992)    Sympathetic overactivity in patients with chronic renal failure, New    England Journal of Medicine, 327(27):1912-1918.-   6. Dibona, Gerald F. and Ulla C. Kopp, (January 1997), Neural    Control of Renal Function, Physiological Reviews, 77(1): 75-197.-   7. DiBona, G. F. (2003), Neural control of the kidney: past, present    and future, Hypertension, 41: 621-624.-   8. Esler, M., Jennings, G., Lambert, G., Meredith, I., Home, M.,    Eisenhofer, (1, (October 1990) Overflow of catecholamine    neurotransmitters to the circulation: source, fate, and functions,    Physiological Reviews, 70(4):963-985.-   9. Ester, M., Schlaich, M., Sobotka, P. et al., (2009)    Catheter-based renal denervation reduces total body and renal    noradrenaline spillover and blood pressure in resistant    hypertension, Journal of Hypertension, 27(suppl 4):s167.-   10. Ester, M. et al., (Dec. 4, 2010), Renal sympathetic denervation    in patients with treatment-resistant hypertension (The Symplicity    HTN-2 Trial): a randomized controlled study, The Lancet, 376:    1903-1909.-   11. Krum, H., Schlaich, M., Whitbourn, R., Sobotka, P. A., Sadowski,    J., Krzysztof, Bartus, K., Kapelak, B., Walton, A., Sievert, H.,    Thambar, S., Abraham, W. T., and Ester, M., (April 2009),    Catheter-based renal sympathetic denervation for resistant    hypertension: a multicentre safety and proof-of-principle cohort    study, The Lancet, 373(9671):1275-1281.-   12, Lu, M., Wei, S. G. and Chai, X. S., (1995), Effect of Electrical    Stimulation of Afferent Renal Nerve on Arterial Blood Pressure,    Heart Rate and Vasopressin in Rabbits, Acta Physiol. Sinica, 47 (5):    471-477.-   13. Ma, G. and Ho, S. Y., (1990), Hemodynamic Effects of Renal    Interoreceptor and Afferent Nerve Stimulation in Rabbit, Acta    Physiol, Sinica, 42 (3): 262-268.-   14. Mahfoud, F., Schlaich, M., Kindermann, I., Ukena, C., Cremers,    B., Brandt, M. C., Hoppe, U. C., Vonend, O., Rump, L. C.,    Sobotka, P. A., Krum, H., Esler, M., and Böhm, M., (May 10, 2011),    Effect of Renal Sympathetic Denervation on Glucose Metabolism in    Patients With Resistant Hypertension: A Pilot Study, Circulation    123(18): 1940-1946.-   15. Medical devices: pg 1-2, Feb. 22, 2012.-   16. Schlaich, M. P., Sobotka, P. A., Krum, H., Lambert, E., and    Ester, M. D., (Aug. 27, 2009), New England Journal of Medicine,    36(9): 932-934,-   17. Schlaich, M. P., Krum, H., Whitbourn, R. et al., (2009), A novel    catheter based approach to denervate the human kidney reduces blood    pressure and muscle sympathetic nerve activity in a patient with end    stage renal disease and hypertension. Journal of Hypertension,    27(suppl 4):s154.-   18. Smithwick, R. H., and Thompson, J. E., (Aug. 15, 1953),    Splanchnicectomy for essential hypertension: results in 1,266 cases,    J Am Med Association, 152(16):1501-1504.-   19. Talenfeld, A. D., Schwope, R. B., Alper, H. J., Cohen, E. I.,    and Lookstein, R. A., Chine 2007), MDCI Angiography of the Renal    Arteries in Patients with Atherosclerotic Renal Artery Stenosis:    Implications for Renal Artery Stenting with Distal Projection,    American Journal of Roentgenology, 188: 1652-1658.-   20. Ueda, H., Uchida, Y., and Kamisaka, K., (1967), Mechanism of the    Reflex Depressor Effect by Kidney in Dog, Jpn. Heart J., 8 (6):    597-606.-   21. Valente, J. F., Dreyer, D. R., Breda, M. A., Bennett, W. M.,    (January 2001), Laparoscopic renal denervation for intractable    ADPKD-related pain. Nephrology Dialysis Transplantation, 16(1): 160.-   22. Vigilance D. W., Mutrie C. J., Yi G. H., Yu K., Guo A., Gelfand    M., Smith C. R., Oz M. C., Levin H., Wang J., (2005), A novel    approach to increase total urine output in acute heart failure:    unilateral renal nerve blockade. Journal of the American College of    Cardiology Supplement 2005, 45(3):166A.-   23. Wang, J., Mapping sympathetic nerve distribution for renal    ablation and catheters for the same, US patent application no.    2011/0306851 A1, filed Aug. 26, 2011.-   24. Ye, S., Zhong, H., Yanamadala, V., Campese, V. M., (August    2002), Renal injury caused by intrarenal injection of phenol    increases afferent and efferent sympathetic nerve activity, American    Journal of Hypertension, 15(8): 717-724.

What is claimed is: 1-19. (canceled)
 20. A system for mapping aparasympathetic or sympathetic nerve underlying the wall of renal vein,comprising: (i) a catheter configured to deliver electrical current toone or more locations on the inner renal vein wall sufficient tostimulate a nerve underlying said renal vein; (ii) one or more measuringdevices for measuring one or more physiological parameters associatedwith said nerve underlying said renal vein, wherein said physiologicalparameters are selected from the group consisting of systolic bloodpressure, diastolic blood pressure, mean arterial pressure, and heartrate; (iii) a computing device configured to couple to the one or moremeasuring devices for computing any increase or decrease in thephysiological parameters against a baseline; and (iv) a display devicefor displaying the location or identity of the parasympathetic orsympathetic nerve underlying said renal vein.
 21. The system of claim20, wherein said catheter could also deliver ablative energy selectedfrom the group consisting of radiofrequency, mechanical, ultrasonic,radiation, optical and thermal energies.
 22. The system of claim 20,wherein said computing device comprises one or more microcontrollers orcomputers.
 23. A method of using the system of claim 20 for mapping aparasympathetic or sympathetic nerve underlying a renal vein, saidmapping comprises: a. introducing the catheter into the lumen of a renalvein such that the tip of said catheter contacts a site on the innerrenal vein wall; b. measuring one or more physiological parameters withthe measuring devices to obtain baseline measurements before introducingelectrical current to the site, said physiological parameters areselected from the group consisting of systolic blood pressure, diastolicblood pressure, mean arterial pressure, and heart rate; c. applyingelectrical stimulation by introducing electrical current to the site viathe catheter, wherein said electrical current is controlled to besufficient to elicit changes in said physiological parameters when thereis an underlying nerve at the site; and d. measuring said physiologicalparameters at a specific time interval after each electrical stimulationwith the measuring device, wherein an increase of said physiologicalparameters over the baseline measurements after said electricalstimulation would be identified by the computing device as mapping of asympathetic renal nerve at said site; a decrease of said physiologicalparameters over the baseline measurements after said electricalstimulation would be identified by the computing device as mapping of aparasympathetic renal nerve at said site; and e. displaying the locationor identity of a parasympathetic or sympathetic nerve underlying saidrenal vein on the display device based on the result of (d).
 24. Themethod of claim 23, said mapping further comprises the step of applyingradiofrequency energy through the catheter to the site identified instep (d) for ablation of the underlying nerve to treat disease caused bysystemic renal nerve hyperactivity.
 25. The method of claim 24, saidmapping further comprises repeating the steps (b) to (d) on the ablatedsite, wherein a lack of change in said physiological parameters confirmsnerve ablation.
 26. The method of claim 23, wherein the electricalcurrent delivered falls within the following ranges: (a) voltage ofbetween 2 and 30 volts; (b) resistance of between 100 and 1000 ohms; (c)current of between 5 and 40 milliamperes; (d) time of applicationbetween 0.1 and 20 milliseconds.
 27. A method of using a catheter formapping parasympathetic or sympathetic renal nerve for treatment ofdisease caused by systemic renal nerve hyperactivity, said cathetercomprises a shaft, the proximal end of said shaft is configured to beconnected to an energy source, and the distal end (catheter tip) of saidshaft is in the form of a single helix, double helix or multiple prongshaving one or more electrodes; said mapping comprises the steps of: a.introducing said catheter into the lumen of a renal vein such that thetip of said catheter contacts a site on the inner renal vein wall; b.measuring one or more physiological parameters to obtain baselinemeasurements before introducing electrical current to the site, saidphysiological parameters are selected from the group consisting ofsystolic blood pressure, diastolic blood pressure, mean arterialpressure, and heart rate; c. applying electrical stimulation byintroducing electrical current to the site via the catheter, whereinsaid electrical current is controlled to be sufficient to elicit changesin said physiological parameters when there is an underlying nerve atthe site; and d. measuring said physiological parameters at a specifictime interval after each electrical stimulation, wherein an increase ofsaid physiological parameters over the baseline measurements after saidelectrical stimulation would indicate that a sympathetic renal nerve hasbeen mapped at said site; a decrease of said physiological parametersover the baseline measurements after said electrical stimulation wouldindicate that a parasympathetic renal nerve has been mapped at saidsite.
 28. The method of claim 27, wherein the electrodes may beactivated independently of one another.
 29. The method of claim 27,wherein the entire catheter is between 1 and 2 m in length, the cathetertip is between 2 and 8 cm in length and between 0.5 mm and 10 mm indiameter.
 30. The method of claim 27, wherein said helix or said prongscomprise coils that are substantially round or flat in shape, and theelectrodes are spaced along the length of said coil or prongs, whereinsaid electrodes are embedded in said coil or prongs, or lie on thesurface of said coil or prongs.
 31. The method of claim 27, wherein thecatheter tip is configured to hold a balloon inflatable to fill thespace within the coil of said helix or prongs.
 32. The method of claim27, wherein said prongs are rejoined at the distal end.
 33. The methodof claim 27, wherein said mapping further comprises the step of applyingradiofrequency energy through the catheter to the site identified instep (d) for ablation of the underlying nerve to treat disease caused bysystemic renal nerve hyperactivity.
 34. The method of claim 33, whereinsaid mapping further comprises repeating the steps (b) to (d) on theablated site, wherein a lack of change in said physiological parametersconfirms nerve ablation.
 35. The method of claim 27, wherein theelectrical current delivered falls within the following ranges: (a)voltage of between 2 and 30 volts; (b) resistance of between 100 and1000 ohms; (c) current of between 5 and 40 milliamperes; (d) time ofapplication between 0.1 and 20 milliseconds.